It is becoming increasingly evident that the etiology of lung cancer involves a combination of both environmental and hereditary factors and that individuals may vary substantially in their genetic susceptibility to carcinogens such as tobacco. The primary goal of this project is to identify individuals genetically predisposed to be at very high risk. To do so we will establish a population-based lung cancer registry consisting of approximately 2 million. We will collect demographic, family history, and smoking data on lung cancer patients and family members. Blood samples will be collected and stored in conjunction with the SPORE Pathology Resource Core (Core B). We will perform segregation analysis on these families to fit genetic and environmental hypotheses and determine the best model characterizing familial aggregation of lung cancer (Aim 1). In doing so, we will also identify specific kindreds which will be useful for subsequent genetic linkage and candidate gene studies. Proband clinical characteristics which may be associated with increased cancer risk to family members will be determined. Sensitivity of peripheral blood lymphocyte DNA to mutagen-induced chromatid breaks will be assessed in lung cancer patients with an without a family history of lung cancer (Aim 2). In addition, we will compare patterns of allele loss in lung cancers from lung cancer patients with a family history of lung cancer and will determine if different patterns of allele loss occur in familial tumors (Aim 3). This part of the project will be closely integrated with Project #3, Molecular Markers for Early Lung Cancer Detection and Project 1, Identification of 3p Recessive Oncogenes in Lung Cancer. Moreover, this project could interact closely with Developmental Project 1 in determining patterns of potential inherited predisposition to nicotine dependency within lung cancer prone families. In addition to addressing the Specific Aims, one of the most important translational applications of this proposal will be the identification of a cohort of asymptomatic individuals who, because of a genetic predisposition, may be candidates for future development of lung cancer chemoprevention trials, a goal of Project #4, or the development of early detection strategies, a goal of Project #3.